Bladder Preservation Strategies for Muscle Invasive Bladder Cancer

Transcription

1 Bladder Preservation Strategies for Muscle Invasive Bladder Cancer Jeff M. Michalski, MD, MBA, FACR, FASTRO The Carlos A. Perez Distinguished Professor of Radiation Oncology Department of Radiation Oncology Washington University School of Medicine St. Louis, Missouri USA

2 Organ conservation in contemporary oncology Anal carcinoma Rectal Cancer Breast carcinoma Esophageal carcinoma Laryngeal carcinoma Limb sarcomas Prostate carcinoma

3 Cystectomy versus ChemoRadiotherapy Comparing cure rates of modern selective bladder preserving approaches with salvage cystectomy to contemporary cystectomy series is difficult. Outcome results are confounded by discordance between clinical (TURBT) staging and pathologic (cystectomy) staging Best approach is to compare the results of prospective protocols in which the eligibility is based on clinical staging and all entered patients are reported for outcome

4 ACS / National Cancer Database ( ): Stage Discrepancy Overall clinical-pathologic stage discrepancy rate was 47.8% and included: 41.9% upstaging at time of surgery 5.9% downstaging at time of surgery 5% of patients with MIBC were downstaged to non-invasive disease Gray et al. IJROBP 2014

5 Percent Discrepancy T-Stage Discrepancy 50 45,4 46, , ,8 10 4,5 5,3 10,3 9,1 0 ct0/tis/ta ct1 ct2 ct3 ct4 Upstaged Downstaged Gray et al. IJROBP 2014

6 Study Population AJCC Clinical Stage AJCC Pathologic Stage III 15% IV 7% I 16% 0 4% IV 25% I 10% 0 4% II 58% III 30% II 31% Gray et al. IJROBP 2014

7 Survival by Stage Discrepancy 1.0 Clinical stage II 1.0 Clinical stage III Surviving fraction Surviving fraction Downstaged Stage agreement Upstaged P < Downstaged Stage agreement Upstaged P < Time (months) Time (months) Gray et al. IJROBP 2014

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10 Medically inoperable An Alternate Approach - Trimodality Therapy TURBT XRT (40Gy) + Concomitant Chemotherapy Cystoscopic response evaluation CR Non-CR Consolidation Chemo-radiation (64Gy) +/- adjuvant chemo Radical Cystectomy +/- adjuvant chemo

11 Long-term Results of TMT Are Excellent MGH Experience (ct2-t4, n=475, f/u 7.2yrs) Giacalone et al. Eur Urol n % Median Age 67 Sex Male % Female % Clinical T Stage ct % ct % ct4a 24 5% Hydronephrosis 57 12% Carcinoma in situ %

12 Long-term Results of TMT Are Excellent MGH Experience (ct2-t4, n=475, f/u 7.2yrs) Neoadjuvant Chemotherapy TURBT Giacalone et al. Eur Urol n % % Visibly complete % Visibly incomplete % Response to induction chemoradiation Complete % Incomplete % Unknown 8 2%

13 Bladder Sparing at MGH by Era Giacalone et al. Eur Urol. 2017

14 Disease-Specific Survival and Overall Survival DSS OS 5-year DSS: 66% 10-year DSS: 59% 15-year DSS: 56% 5-year OS: 57% 10-year OS: 39% 10-year OS: 25% Giacalone et al. Eur Urol. 2017

15 Cox Regression Analyses for Overall Survival European urology by EUROPEAN ASSOCIATION OF UROLOGY Reproduced with permission of ELSEVIER HEALTH SCIENCE JOURNALS in the format Post in a course management system via Copyright Clearance Center. Giacalone et al. Eur Urol. 2017

16 TURBT and Salvage Cystectomy Key to Success of TMT Maximal Complete TURBT Giacalone et al. Eur Urol. 2017

17 RTOG Experience 6 trials (5 phase II, 1 phase III) 468 Patients Median FU 4.3 years overall, 7.8 years for survivors

18 Disease-specific Survival(%) Does age matter? Pooled RTOG MIBC Studies DSS for Age < 75 vs. Age % 70% 65% 64% 25 Patients at Risk Age < 75 Age >=75 0 Age < 75 Age >=75 Failed Total p= 0.84(Gray) Years after Randomization Mak et al. J Clin Oncol 2014; 32:

19 Long-term Cystectomy & PLND Results USC & U. Bern ; ; 959 patients pt2-3, cn0, cm0, median F/U 10 yrs (10 yrs. 60%) Zehnder, Studer, Skinner et al. J Urol 2011

20 Survival After Curative Therapy Stein (2001) J Clin Oncol Dalbagni (2001) J Urol 2001 Grossman (2003) N Engl J Med Shipley (1998) J Clin Oncol1998. Rodel (2002) J Clin Oncol Giacalone Eur Urol 2017 James et al. N Engl J Med Mak et al. J Clin Oncol 2014

21 Selection is Key Tumor presentations with the highest success rates: Solitary T2 or early T3 tumors < 6 cm No tumor-associated hydronephrosis Tumors allowing a visibly complete TURBT Invasive tumors not associated with extensive carcinoma in situ Adequate renal function to allow cisplatin concurrent with radiation TCC histology

22 Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic Kulkarni PMH JCO 2017

23 Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic Kulkarni PMH JCO 2017

24 Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic Kulkarni PMH JCO 2017

25 MRC SPARE Bladder Protocol TURBT Gemcitabine and Cisplatin 3 cycles Cystoscopic assessment of treatment response Incomplete response Complete response Definitive Radiation + Chemo Closed March 2010 with only 4% of cases Huddart et al BJU Int 2010

26 Which chemotherapy with radiation?

27 Role of Concurrent Chemotherapy The active radiosensitizing drugs include: Cisplatin, 5-FluoroUracil, Mitomycin C, Paclitaxel, Gemcitabine

28 University of Erlangen Experience n CR RT alone 98 57% RT + carboplatin 69 64% RT + cisplatin % RT + 5-FU/cis 45 87% Rodel et al. IJROBP 2002;52:1303-9

29 Concurrent Chemotherapy + Twice-Daily RT Protocol Induction treatment Patients Complete Response TURBT, 5-FU plus 34 67% CP + BID RT TURBT, CP + BID RT 52 74% adj MCV TURBT, TAX plus 80 81% CP + BID RT adj CP + GEM

30 RTOG PROTOCOL 0233 (Randomized Phase II) (PI: AL Zietman, MD) Stage T2 T4a, No Hydronephrosis Candidate for cystectomy, if necessary TURBT randomization bid RT 5FU Cisplatin bid RT Paclitaxel Cisplatin Finished accrual patients

31 RTOG 0233 Bladder-intact survival by treatment arm Mitin T, Hunt, D, Zietman, A et al. Lancet Oncol 2013

32 RTOG PROTOCOL 0712 (Randomized Phase II) Stage T2 T4a, No Hydronephrosis Candidate for cystectomy, if necessary TURBT randomization RTOG (FCT): bid RT 5FU 400mg/m2 Cisplatin 15mg/m2 Michigan (GD): qd RT Gemcitabine 27mg/m2 Started accrual 2008, closed 2014

33 RTOG PROTOCOL 0712 (Randomized Phase II) Following ChemoRadiotherapy, patients received adjuvant Gem/Cis

34 NRG/RTOG patients enrolled, 66 eligible for analysis Regimen CR Gr 3/4 tox FCT 22% 67% 88% 64% GD 16% 72% 78% 54% Once daily RT (GD) was as effective as BID Toxicity was less with GD Coen ASTRO 2017

35 Role of Neoadjuvant Chemotherapy No Level 1 (Phase III) data indicating cisplatin-based neoadjuvant chemotherapy given before definitive local treatment by RT or RT and concurrent chemotherapy significantly improves survival. RTOG trial (n=123) negative (5 year survivals of 49% and 50%) Danish Cancer Group trial (n=113) negative (NCT had 5.6% lower survival) RT subgroup of MRC trial (n=413) trended insignificant in favor of NCT Meta-analysis negative (survival 30.4% vs 28.1%)

36 James NEJM 366: , 2012

37 Phase III randomized trial of synchronous chemo-radiotherapy compared to radiotherapy alone in muscle invasive bladder cancer (BC2001 CRUK/01/004) 360 patients clinical stage T2-4aNx bladder cancer XRT 55 Gy/20 or 64 Gy/32 RT + MMC & 5-FU GFR > 25 ml/min Median follow-up 49 months James et al NEJM 2012

38 U. K. Chemotherapy regimen for MIBC MMC 12mg/m2 5FU 500mg/m2/d RT 55 Gy/20 f or 64 Gy/32 f Weeks James et al NEJM 2012

39 LRDFS with & without chemotherapy yr LRDFS 67% (95% CI: 59%, 74%) 54% (95% CI: 46%, 62%) HR = 0.66 (95% CI: 0.46, 0.95); p=0.02 CT = 52/182 No CT = 74/ Months since randomisation N at risk (events) CT 182 (34) 106 (14) 71 (2) 51 (1) 41 (1) 23 (0) 11 No CT 178 (53) 94 (16) 62 (4) 48 (0) 25 (0) 18 (1) 9 James et al NEJM 2012

40 Invasive loco-regional disease free survival with and without concurrent chemotherapy 2-yr ILRDFS 82% (95% CI: 75%, 88%) CT=28/182 68% (95% CI: 59%, 75%) No CT=51/178 HR = 0.53 (95% CI: 0.33, 0.84); p= Months since randomisation N at risk (events) CT No CT 182 (20) 118 (6) 88 (2) 61 (0) 48 (0) 30 (0) (35) 108 (13) 77 (2) 59 (1) 29 (0) 19 (0) 11 James et al NEJM 2012

41 OS in chemotherapy randomisation 2-yr OS 62% (95% CI: 54%, 68%) CT = 85/182 60% (95% CI: 52%, 67%) No CT = 98/178 HR = 0.81 (95% CI: 0.60, 1.09); p= Months since randomisation N at risk (events) CT 182 (35) 141 (33) 104 (10) 72 (4) 56 (1) 37 (1) 18 No CT 178 (35) 139 (34) 95 (14) 68 (12) 33 (3) 19 (0) 11 James et al NEJM 2012

42 Quality of life after chemo-radiation

43 Late Pelvic Toxicity: RTOG Results 157 patients with bladder preservation who survived 2 to 13 years (median follow-up 5.2 years) 22% Grade 1 10% Grade 2 7% Grade 3 (5.7% GU, 1.9% GI) 0% Grade 4 0% Grade 5 Efstathiou et al J Clin Oncol 2009

44 MGH Urodynamics and QOL Study 221 patients treated with TMT on protocols , median follow-up 6.3 years 78% have compliant bladders with normal capacity and flow parameters 85% have no or occasional urgency 25% have occasional to moderate bowel control symptoms 50% of men have normal erectile function Zietman AL, et al. J Urol 2003

45 GETUG Prospective Phase II study of 51 MIBC patients treated with TMT , without disease relapse, median follow-up 8 years Mean global QOL, physical, emotional, personal, cognitive, and social function scores >70% 100% satisfactory bladder function 70% maintained bladder function scores 1 year after treatment 79% had sexual activity 18 months after treatment (vs. 56% pre-treatment) Lagrange JL, et al. IJROBP 2011

46 MGH/UNC: Long-Term QOL Cross-sectional study of 173 patients diagnosed in , disease-free for 2 years Treated at high-volume, academic medical centers with modern techniques Median follow-up: 5.6 years - 63% patients received cystectomy (n=109) - 82% ileal conduit and 18% neobladder diversions - 37% received TMT (n=64 ) - 9% required salvage cystectomy (n=6) Six validated QOL questionnaires, scored out of 100 Mak et al. IJROBP 2016

47 Validated Instruments General HRQOL: 1) EuroQOL EQ-5D: 3L and visual analog scale 2) European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) Symptom-specific HRQOL: 3) EORTC MIBC module (QLQ-BLM30) 4) Expanded Prostate Cancer Index Composite - Bowel Assessment (EPIC) Perception and Impact of Cancer: 5) Cancer and Treatment Perception Scale 6) Impact of Cancer Version 2 (IOCv2) Each instrument scaled to score Mak et al. IJROBP 2016

48 MGH/UNC: Long-Term QOL Both cystectomy and TMT associated with good long-term QOL outcomes Compared to RC, TMT associated with: Modestly higher general QOL (by 7-10 points) Similar urinary scores Modestly higher bowel function (by 3-7 points) Markedly better sexual QOL (by 9-32 points) Better informed decision-making (by 14 points) Less concerns about appearance (by 14 points) Less life interference from cancer or cancer treatment (by 9 points) Mak et al. IJROBP 2016

49 Mak et al. IJROBP 52016

50 Mak et al. IJROBP

51 ICUD-EAU Bladder Cancer Guidelines In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC Gakis et al. Eur Urol 2012

52 Acceptance of chemoradiation used in modern bladder-sparing therapy should not be limited by concerns of high rates of late pelvic toxicity

53 Closing Thoughts Combined modality therapy achieves a CR and preserves the native bladder in ~70% of patients, while offering long-term survival rates comparable to contemporary radical cystectomy series QOL studies have demonstrated that the retained native bladder functions well and long-term toxicity of chemort to pelvic organs is relatively low Incidence of cystectomy performed for palliation of treatment-related toxicity has been very low and the morbidity of salvage cystectomy appears comparable to primary cystectomy

54 Closing Thoughts The contribution of selective bladder sparing therapy to the quality of life of patients represents a unique opportunity for urologic surgeons, radiation oncologists, and medical oncologists to work hand in hand in a truly multidisciplinary effort

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